4, 21-dihalo-17alpha-hydroxypregnane-3, 11, 20-trione



U i ed. ta es Pa e Upjohn Company, Kalamazoo, Mich., a corporation ofMichigan No Drawing. Application July 14, 1953, Serial No. 367,984

4 Claims. (Cl. 260-39745) The present invention relates to steroidcompounds and is more particularly concerned with thenovel 4,2l-dihalo-17a-hydroxypregnane-3,11,20-triones which may be represented by theformula:

wherein X is selected from the group consisting of chlorine and bromine,the provision of these compounds being the main object of thisinvention. These compounds can be prepared by halogenation of theappropriate 3,11,17,20-

tetra-oxygenated steroids.

The 4,21-dihalo compounds of the present invention are particularlyuseful since they can be converted to cortisone 21-acylates wherein the21-acylate is very sensitive to chemical reagents. This is possiblebecause the products of the present invention can be converted tocortisone Zl-acylates by a process in which the 2l-acylate is introducedas the last step, as shown in Example 1. Cortisone 21-acrylate, forexample, can be conveniently prepared by the process of the presentinvention, but cannot be readily prepared by prior art procedures forthe preparation of cortisone 21-acylates from halo-steroids whichrequire, after introduction of the 21-acylate, the formation of a4-double bond by halogenation and subsequent dehydrohalogenation, sincethe 21-acrylate would react during these subsequent steps, e. g., the21- acrylate would add halogen. Other objects and uses of the presentinvention will be apparent to one skilled in the art to which thisinvention pertains.

The following examples are illustrative of the products of the presentinvention but are not to be construed as limiting.

Example 1 .4,21-dib2 '0m0-17m-hydroxypregnane- 3,1 1 ,20-tri0ne Tengrams (10 grams) of l7a-hydroxy-2l-bromopregmane-3,11,20-trione, meltingpoint 213 to 215 degrees centigrade (decomposition), dissolved in amixture of 250 milliliters of acetic acid and 150 milliliters ofmethylene dichloride, is brominated at room temperature using a solutionof 3.96 grams of bromine in 54 milliliters of acetic acid. The bromineis added dropwise, with continuous stirring, allowing sufiicient timefor each drop to be decolorized before adding subsequent drops. Afterthe total amount of bromine has been added, the mixture is poured intoone and one-half liters of water and the methylene dichloride layer isseparated. The water layer I, 2,778,842 Patented Jan. 22, 1957-droxypregnane-B,11,20-trione and 1.32 grams of semicarbazidehydrochloride in 42 milliliters of dioxane and 8.5 milliliters of wateris stirred for a period of one hour at room temperature (about 26degrees centigrade). Four milliliters of pyruvic acid and fivemilliliters of water are added, and the solution is heated for one hourat sixty degrees centigrade. The resulting mixture is poured into oneliter of water and extracted with methylene dichloride. After washingwith water, dilute aqueous sodium hydroxide solution, and again withwater, the solution is dried over anhydrous sodium sulfate and, afterremoval of the drying agent, the solvent distilled. The residueremaining is recrystallized from milliliters of acetone to give21-bromo-l7a-hydroxy-4-pregnene- 3,11,20-trione of melting point 225 to245 degrees centigrade (decomposition).

The 2l-bromo-17u-hydroxy-4-pregnene-3,1 1,20-trione can be converted tocortisone acetate (17a-hydroxy-2l, acetoxy-4-pregnene-3,11,20-trione) asfollows:

One gram of 17a-hydroxy-21-bromo-4-pregnene-3,ll,- 20-trione, dissolvedin 200 milliliters of acetone, is heated under reflux for a period ofseventeen hours with 1.2 grams of anhydrous potassium acetate, a fewsmall crystals of potassium iodide, and one milliliter of glacial aceticacid. The reaction mixture is then cooled, and the inorganic saltsremoved by filtration. Evaporation of the solvent from the filtrategives white needles of 17a-hydroxy-21-acetoxy-4-pregnene-3,11,20-trione(cortisone acetate) of melting point 210 to 220 degrees centigrade.Recrystallization from acetone gives pure cortisone acetate of meltingpoint 234 to 237 degrees centigrade.

Example 2.4-chl0r0-1 7a-hydr0xy-21-brom0pregnane- 3,11,20-tri0ne Asolution of two grams of 30:,17u-dihYd10XY-2l-b1'0-m0pregnane-11,20-dione, melting point 178 to degrees centigrade, infifty milliliters of tertiary-butyl alcohol containing 1.5 millilitersof water and 0.38 milliliter of concentrated hydrochloric acid isreacted with 1.12 milliliters of tertiary-butyl hypochlorite for 3.5hours, at the end of which time the hypochlorite is completely consumed.The solution is then diluted with twice its volume of water whereuponthe theoretical 2.17 grams of 4-ch1oro 17ahydroxy-Zl-bromopregnane-3,11,20-trione precipitates, melting point 168to 174 degrees centigrade.

Analysis.Calculated for C21HzaClBrO4: Total halogen, 25.10. Found: Totalhalogen, 24.42.

4-chloro-17a-hydroxy-21-bromopregnane-3, 1 1,20-trione also is obtainedin exactly the same manner as above using the same reactants butsubstituting tertiary-amyl hypochlorite for the tertiary-butylhypochlorite. 4-chloro- 17a-hydroxy-2l-bromopregnane-3,11,20-tri0ne is astable compound and does not decompose on standing. The presence of ahalogen atom at carbon atom 4 and at carbon atom 21 renders the compounda valuable precursor to known physiologically active cortical hormones.Dehydrohalogenation with semicarbazide hydrochloride followed by pyruvicacid gives 17a-hydroxy-2l-bromo-4- prcgnene-'3;1'1,20=trione. Subsequenttreatment with -130- tassium acetate in acetone gives cortisone acetate.

.Example 3.4,2l-dichloro-lZu-hydroxypregnane-3,1l,- -20-trione Treatmentof 3a,17a-dihydroxypregnane 1 1,ZO-dione [Sarett, -J. Chem. Soc, 70,1454 ("1948 with chlorine-in acetic acid is productivedf30:,17a-dlhYdl'OXY-21- chloropre'gnane-l1,20-dione. In the samemannera's described in Example 2,-Teacting 304,17oc-dihYClIOXY-21-Chl0-ropregnane-'l'1;20-d-ione with 'tertiary-butyl hypochlorite intertiary-butyl alcohol in the presence of water and hydrochloric acid'isproductive of 4,21-dich1oro-l7a-hydrxypregnane- 3,=I1,20=trione "in highyield. 4,21-dichloro-17a-hydroxypregnane-3,11,20-trione is 'a stable,welldefined crystalline solid which does not decompose on standing."Dehydrohalogenation followed by treatment withpotassium acetategivescortisone acetate as in Extamplez.

Example 4.--.4.-chl0r0-2] -br0m0=1 7m-hydroxypregnane- 3,11,20-trioneFollowingthe method of Example2, 21'-bromo-3a,1 1a,- 17a-trihydroxypregnane-2O-one, melting-point 123 to 1-25 degreesCentigrade, gives 4-chloro-21-bromo-11a,l'7ocdihydroxy=pre'gnane-3,ZO-dione in excellent yield. Mild oxidation of thel la-hy'clroxy group of 4-chloro-21-brom0- 11at,17z-dihydroxypregnane-3,2()-dione gives 4=chloro 21bromo-l7ouhydr0xypregnane-3;1-1,20-trione, melting at 169 to 174-degrees centigrade, which can be converted to cortisone acetate asshownin Example '2. Chlorination of2l-bromo-l7a-hydroxypregnane-3,11,20-trione with chlorine'in acetic acidalso is productive 'of-4 chloro-2l- 'bromo 17a-hydroxypregnane-3 ,11,20-trione.

The 4,21-dihalo-17u-hydroxypregnane-3,11,20-trionesofthepresentinventionmay"also beprepared from"other suitable3,11,17,20-tetra-oxygenated steroids using appropriate halogenationprocedures. It is to be understood, therefore, that the invention is notto be limited to the exact details of operation 'orexact compounds shownand described .as obvious modifications and ,eguiv-alents will beapparent to one skilledin itheart and the invention is therefore to belimited only by the scope of the appended claims.

This application is a continuation-impart of our :00- pendingapplications, Serial .Numbers 2992321299233; and 299,234 now Patent Nos.2,714,599; 2,714,650; :and 2,714,601, respectively; each filed July 16,1952.

We claim:

1. A 4,21-dihalo 17a hydroxypregnane-3,11,20-trione selected from the.;group iconsistingof 4,2-l-dlChl0I'O-l7ahydroxypregnane 3,11,20 trione,4,21 dibromo 17cchydroxypregnane, 3,11,20-trione, and-4-chloro-21-brom0-l-lmhydroxypregnane-3,1.1,20@trione.

.2. 4,21-dichloro=1la-hydroxypregnanerl-l-l,20wtrione.

3. 4,2l-dibromo-17a-hydroxypregnane 3,1'1,20 trione.

4. 4 chloro 21 bronio 17oz hydroxypregnane- 3,1 1,20-trione.

References :Gited in the file of this patent UNITED \STATES PATENTSMarker Feb. 6, 1945 Clinton Aug. 10, 1954 OTHER REFERENCES (January

1. A 4,21-DIHALO-17X-HYDROXYPREGNANE-3,11,20-TRIONE SELECTED FROM THEGROUP CONSISTING OF 4,21-DICHLORO-17AHYDROXYPREGNANE - 3,11,20 - TRIONE,4,21-DIBROMO - 17AHYDROXYPREGNANE, 3,11,20-TRIONE, AND4-CHLORO-21-BROMO1MX-HYDROXYPREGNANE-3,11,20-TRIONE.